Pharmacology of Depression

Question 1

What are the 5 most common, main drug classes prescribed for depression?

Answer 1

1. Sertraline
2. Citalopram
3. Fluoxetine
4. Venlafaxine
5. Mirtazapine

Question 2

What is the primary mechanism of action for Sertraline?

Answer 2

SSRI

Inhibition of serotonin reuptake results in an accumulation of serotonin

Serotonin in CNS = role in regulation of mood, personality, and wakefulness

Question 3

What is the drug target site for Sertraline?

Answer 3

Serotonin transporter

Question 4

What are the main side effects for Sertraline?

Answer 4

GI effects - nausea, diarrhoea
Sexual dysfunction
Anxiety
Insomnia

Question 5

What is some extra information about Sertraline?

Answer 5

Mild inhibition of dopamine transporter

Must be gradually decreased on discontinuation.

Partial inhibition of CYP2D6 at high doses (150 mg)

Question 6

What is the primary mechanism of action for Citalopram?

Answer 6

SSRI

Inhibition of serotonin reuptake results in an accumulation of serotonin

Serotonin in CNS = role in regulation of mood, personality, and wakefulness

Question 7

What is the drug target site for Citalopram?

Answer 7

Serotonin transporter

Question 8

What are the main side effects for Citalopram?

Answer 8

GI effects - nausea, diarrhoea
Sexual dysfunction
Anxiety
Insomnia

Question 9

What is some extra information about Citalopram?

Answer 9

Mild antagonism of muscarinic and histamine (H1) receptors

Must be gradually decreased on discontinuation

Metabolized by CYP2C19.

Question 10

What is the primary mechanism of action for Fluoxetine?

Answer 10

SSRI

Inhibition of serotonin reuptake results in an accumulation of serotonin

Serotonin in CNS = role in regulation of mood, personality, and wakefulness

Question 11

What is the drug target site for Fluoxetine?

Answer 11

Serotonin transporter

Question 12

What are the main side effects for Fluoxetine?

Answer 12

GI effects - nausea, diarrhoea
Sexual dysfunction
Anxiety
Insomnia

Question 13

What is some extra information about Fluoxetine?

Answer 13

Mild antagonism of 5HT2A and 5HT2C receptors

Complete inhibition of CYP2D6 and significant inhibition of CYP2C19 (caution with warfarin)



Question 14

What is the primary mechanism of action for Venlafaxine?

Answer 14

SNRIs

Venlafaxine is a more potent inhibitor of serotonin reuptake than norepinephrine reuptake

Noradrenaline in CNS = implicated in regulation of emotions and cognition

Question 15

What is the drug target site for Venlafaxine?

Answer 15

Serotonin transporter

Noradrenaline transporter

Question 16

What are the main side effects for Venlafaxine?

Answer 16

GI effects - nausea, diarrhoea
Sexual dysfunction
Anxiety
Insomnia
Hypertension - at higher doses

Question 17

What is some extra information about Venlafaxine?

Answer 17

Must be gradually decreased on discontinuation

Question 18

What is the primary mechanism of action for Mirtazapine?

Answer 18

Antagonises central presynaptic alpha-2-adrenergic receptors, which causes an increased release of serotonin and norepinephrine

Antagonises central 5HT2 receptors, which leaves 5HT1 receptors unopposed causing anti-depressant effects

Question 19

What is the drug target site for Mirtazapine?

Answer 19

Alpha-2 receptor

5-HT2 receptor

Question 20

What are the main side effects for Mirtazapine?

Answer 20

Weight gain

Sedation

Question 21

What is some extra information about Mirtazapine?

Answer 21

Low probability of sexual dysfunction. May exacerbate REM sleep behaviour disorder

Question 22

What is the 7-step process to a clinical scenario / consultation?

Answer 22

1. Identify the patient’s problem
2. Specify the therapeutic objective
3. Select a drug on the basis of comparative efficacy, safety, cost and suitability
4. Discuss choice of medication with patient (and carer) and make a shared decision about treatment
5. Write a correct prescription
6. Counsel the patient on appropriate use of the medicine
7. Make appropriate arrangements for follow up (Monitor/stop the treatment)

Question 23

Curtis Nash - 47M = recently diagnosed with hypertension and prescribed losartan (angiotensin 2 receptor blocker (25mg once daily). BP remains high at 147/91mmHg even after a month.

Low mood, anhedonia, low self-esteem. Difficulty getting to sleep, inability to think clearly, describing a ‘fog’ in his head. Symptoms persistent over a month, put a strain relationship with wife and job performance as a teacher.

Patient Health Questionnaire 9 (PHQ-9) = 9 item questionnaire designed to screen for depression in primary care.
Curtis scored 14/27

What is the patient’s problem?

Answer 23

He has MDD
He is moderately depressed according to his PHQ-9 score

So he has moderate MDD

Question 24

What is the therapeutic objective for this patient?

Answer 24

1. Alleviate his depressive symptoms - improve mood, anhedonia, sleep difficulties, self-esteem, think clearly
2. Reduce likely functional impairment depressive symptoms on his daily life - improve relationship with wife and job performance (usually comes along with alleviating depressive symptoms)

Question 25

Despite GP informing Curtis of the benefits of counselling, self-help programmes and CBT, Curtis wants a ‘pill’ to treat his depression. GP informs him of different types of anti-depressants and their side effects. Recommends SSRI = fewer side effects. He is on anti-hypertensive (Losartan) and low dose erythromycin to treat chronic prostatitis. What is the mechanism of action of SSRIs?

Answer 25

CNS serotonin AKA 5-HT = regulation of mood, personality, wakefulness ``` 5-HT = 5-hydroxytriptamine 5-HTT = 5-hydroxytriptamine transporter ``` So the SSRIs inhibit the 5-HTT in the pre-synpatic neuron to increase the 5-HT in the synapse More serotonin acts on the post-synaptic neuron, improving mood, personality and wakefulness

Question 26

For SSRIs: What is the target? What is the location? What is the effect?

Answer 26

5-HTT On the pre-synaptic neuron Increased serotonin availability

Question 27

The three most commonly prescribed SSRIs are: Sertraline Citalopram Fluoxetine Considering Curtis' medical history, which drug would you avoid?

Answer 27

Both, erythromycin and citalopram as they prolong the QT interval This would not be good for his CV issues

Question 28

GP prescribes sertraline, 50mg orally once a day. It takes some time to work, may experience side effects before this. Urges him to take it until his next appointment in two weeks. The data above shows the effect of increasing the SSRI dose on (i) reduction in depression rating and (ii) dropouts due to adverse effects. The study has established equivalence dosing e.g. 50mg sertraline is equivalent to 20mg fluoxetine. What are the key take home messages from the data in the two dose response curves above?

Answer 28

First graph (i) = peak at 30 mg of fluoxetine, and then a plateau at higher doses (only a small improvement with the SSRIs alone) Second graph (ii) = exponential increase in dropouts due to adverse effects

Question 29

Why might the effectiveness of the SSRIs plateau after the peak dosage?

Answer 29

Receptor-saturation Due to finite number of receptors, so there will be excessive 5-HT in the synapse as all the receptors are occupied

Question 30

Curtis does not see an improvement with Sertraline. Why does the GP taper him off the sertraline slowly, and wait a period of time before starting the next drug?

Answer 30

Withdrawal symptoms or relapse if not slowly tapered off Wash out period - without this may lead to 'serotonin syndrome' = too much excitability

Question 31

Two regularly prescribed anti-depressants are venlafaxine and mirtazapine. What are the drug targets for these?

Answer 31

Venlafaxine: Transport proteins - serotonin transporter and noradrenaline transporter Leads to increased serotonin and noradrenaline Mirtrazapine: Receptors - antagonist of the: Alpha-2 receptor, Histamine H1 receptor, 5-HT2 receptor and 5-HT3 receptor Leads to increased noradrenaline Affects on H1 receptor can make you drowsy but that may help with the sleep

Question 32

Revisit Curtis’ presenting history. Which drug – venlafaxine or mirtazapine – should the GP prescribe next and why?

Answer 32

Venlafaxine = noradrenaline transporter inhibitor Increased noradrenaline may increase BP, and may not help his sleeping difficulties Mirtazapine = H1 antagonist = sedation This can help his sleep and will not adversely affect his BP Although it does suppress his REM sleep slightly

Question 33

GP prescribes mirtazapine - 15mg, orally once daily. 4 weeks later, Curtis feels improvement. Explain the data found in this table in terms of selectivity, affinity and efficacy: ``` Highest affinity H1 receptor = sedation Alpha-2 receptor = anti-depressant effect 5HT2 receptor = antidepressant effect 5HT3 receptor = anti-emetic Lowest affinity ```

Answer 33

Selectivity = not very selective Affinity shows that sedative effects come in before anti-depressant and anti-emetic effects At low doses = sedative effects At higher doses = noradrenaline effects helps counteract sedative effects Efficacy = no efficacy as they are antagonist, they block actions of receptors

Question 34

Why does Curtis need to be monitored regularly?

Answer 34

Compliance - may be affected due to lack of libido, weight gain etc. May start feeling better and stop taking them